The present invention is related to the prolonged release of an active agent from a dosage form. More particularly, it relates to a dosage form, containing a liquid, active agent formulation, the dosage form being adapted to be retained in the stomach for a prolonged period of time, during which a liquid, active agent formulation is released to the environment of use.
Controlled release dosage forms that provide for prolonged delivery of active agent formulations to the environment of use have found application for increasing numbers of active agents. However, it has generally been a problem to deliver liquid, active agent formulations to the stomach of a subject continuously or intermittently over a prolonged period of time. Particularly when the active agent is absorbed only in the upper gastrointestinal tract, the bioavailability of the active agent may be greatly reduced if it is rapidly released from the stomach and passes quickly through the upper gastrointestinal tract. The period of time for absorption may be too short for an effective amount of active agent to be absorbed over a reasonable period of time, without frequent, subsequent dosing. This is particularly a problem with liquid forms of active agents, since they tend not to be retained within the stomach for more than a short period of time. Instead they tend to pass quickly from the stomach, through the upper gastrointestinal tract and into the lower gastrointestinal tract.
Generally, the time of passage of different particles through the small intestine does not vary significantly, and passage is generally independent of food intake and particle size. Thus, active agent dissolved in liquid, solid active agent dispersed in liquid and relatively larger delivery units of active agent, such as microcapsules and the like, will traverse the length of the small intestine in substantially the same time frame, usually about 3-5 hours. However, if liquid active agents can be retained in the stomach and released over a prolonged period of time, the active agent can be delivered to the small intestine over a time much longer than the 3-5 hour window, increasing the likelihood of increased absorption.
Most active agents are not well absorbed in the stomach, but even in those instances where the active agent is not well absorbed, the continuous release of active agent in the stomach over a prolonged time period will dispense active agent over that same period of time to the small intestine where it can be absorbed.
The physiological behavior of the stomach is usually determined by whether it contains food or is empty. Food is mixed and partially digested in the distal stomach (antrum). As the stomach undergoes contractions, partially digested material is discharged into the small intestine and non-digested material is retropelled into the main part of the stomach for further digestion. In the fed state, non-digestible material is not generally able to leave the stomach. At the end of a digestive period, the stomach enters the fasting stage and begins a cycle called the interdigestive myoelectric motor cycle or IMMC.
The IMMC can be considered to be divided into four phases: (1) phase 1 is an approximately one hour period with no contractions; (2) phase 2 is about a forty minute period of intermittent potentials and contractions that increase in intensity over time; (3) phase 3 is a relatively short period, generally between about five to fifteen minutes, of intense contractions (commonly called the xe2x80x9chousekeeper wavexe2x80x9d) that completely empties the stomach; and (4) phase 4 is a short transitory period between the intense activity of phase 3 and the quiescence of phase 1. The different phases move distally from the stomach to the terminal ileum over an approximately two hour period as the cycle is repeated. Since the cycle is interrupted by the receipt of food by the stomach, it is possible to delay the emptying phase, phase 3, by maintaining a fed state. However, it is not practical to regularly maintain the fed state over a long period of time. Consequently, a need exists for a delivery device that can remain in the stomach for a significant period, whether in the fed or fasted state, and deliver active agent to the stomach over a prolonged period of time.
A variety of studies have been conducted in dog and in man to determine sizes of objects that would be retained in the stomach during the fed stage and also in the fasting stage when IMMC is present. Khosla and Davis, International Journal of Pharmaceutics, Vol. 62 (1990), pages R9-R11 have reported that a particle size less that 2 mm generally results in emptying from the stomach of the dog. Non-disintegrating tablets having sizes of 7, 11 and 13 mm in diameter were emptied from the human stomach, but the larger sized tablets tended to remain in the stomach longer than the small sized tablets. Tablets larger than 11 mm tended to be emptied only during the IMMC. Davis et al., Pharmaceutical Research, Vol. 8, No. 10 (1991) has described retention of radio-telemetry capsules having a size of 25xc3x978 mm in the stomach of human subjects past phase 3 of the IMMC. Timmermans et al., Journal of Pharmaceutical Sciences, Vol. 82, No. 8 (1993) has reported the mean resting pyloric diameter in humans as 12.8xc2x17.0 mm. Accordingly, it is important that gastric retentive delivery vehicles are adapted to disintegrate, dissolve or erode to sizes that permit eventual elimination of the vehicle without causing gastric obstruction.
The influence of food on gastric retention time and the absorption of acyclovir has been reported in International Journal of Pharmaceutics, Vol. 38 (1987), pages 221-225. As reported there, compared to a lighter meal, the heavier meal slowed the rate of gastric emptying, prolonged small intestinal transit time and decreased absorption of the active agent.
Various attempts to provide active agent delivery devices that remain in the stomach for extended periods or time have been described previously. For example, U.S. Pat. No. 4,851,232 describes a hydrogel reservoir containing tiny pills having a active agent core surrounded by a wall controlling delivery of active agent to the stomach. The hydrogel swells in the stomach to facilitate retention of the active agent reservoir in the stomach over time.
U.S. Pat. No. 4,871,548 describes a dosage form including a mixture of low and high number average molecular weight hydroxypropyl methylcellulose polymers and active agent that swells when in the stomach.
U.S. Pat. No. 4,767,627 describes substantially planar devices formed of bioerodible polymer including active agent that may be compressed and folded for oral administration and then released and unfolded in the stomach, where the devices are to be retained over an extended period of time. The devices have a longest diameter of between 1.6 and 5 cm. It is suggested that as an alternative to incorporating the active agent into the device a controlled release active agent module, mechanically or osmotically driven, can be glued or tethered to the device.
U.S. Pat. No. 5,443,843 describes a plurality of compressible retention arms and an attached controlled release device which in the expanded form resists gastrointestinal transit. The system can have a collar or a belt for receiving and holding a active agent-containing, orally-administrable controlled release device. In a fully expanded configuration for human use, the system is described as having minimum and maximum dimensions of 2.5 and 6.0 centimeters, respectively.
U.S. Pat. No. 5,007,790 describes a sustained release active agent dosage form in the form of a capsule or tablet that includes a plurality of hydrophilic water-swellable, cross-linked polymer particles that swell in the stomach to promote gastric retention and permit gastric fluid to penetrate the particles to dissolve active agent and deliver it to the stomach in the solution state. The particles are indicated to retain their physical integrity over the dosing period. Initially sized particles, indicated to be preferably spherical, are disclosed to be in the range of 50 xcexcm to 2 mm, swell to a size of about 3 mm. A plurality of particles are packed into a capsule for administration to a patient.
U.S. Pat. No. 5,582,837 describes a dosage form similar to that of U.S. Pat. No. 5,007,790, without the use of a cross-linked hydrophilic polymer. The particles are described as slippery and soft, preferably spherical, and having dimensions on the order of 6 to 18 mm in the swollen state. The particles can be packed into capsules containing 7-25 spherical particles, depending on the size, or formulated into tablets that contain from 2-25 spherical particles.
The use of albumin-cross-linked polyvinylpyrrolidone hydrogels to deliver flavin mononucleotide to dogs has been described by Park et al. in Journal of Controlled Release, Vol. 19 (1992) pages 131-134. The hydrogels were maintained in the stomachs of dogs for extended periods, even in the fasted state. Gels with a glassy core tended to remain in the stomach longer than hydrogels without the glassy core. Control of the size of the core was attempted by administration of water in the stomach. While it is possible to control the dimensions of the hydrogel in the dry state, controlling the size of the glassy core within the hydrogel after administration to a subject by addition of water is not suitable for fabrication of a dosage form that can routinely and controllably be retained in the stomach of a subject over a prolonged period of time.
While it is important that the delivery device be adapted to remain in the stomach for a prolonged period, it is also important that the device deliver active agent in a controlled manner. Delivery systems, such as those described below, are representative of the many different systems have been suggested for such controlled delivery of active agents over a prolonged period of time.
For example, U.S. Pat. No. 4,290,426 to Lusted et al describes a cylindrical dispenser for releasing a beneficial agent into a fluid environment at a rate that is governed by the fluid induced relaxation of a polymeric agent contained within the dispenser. The cylindrical dispenser includes an impermeable container that has within it a reservoir and a passageway from the reservoir to the exterior of the container. The reservoir contains a polymer and a beneficial agent. The polymer imbibes fluid from the environment and thereby undergoes relaxation, releasing the beneficial agent from the device. The amount of agent released is dependent on the rate of relaxation of the polymer over time.
Coated dosage forms have also been suggested for delivery of a controlled amount of a beneficial agent over a prolonged period of time. U.S. Pat. No. 5,256,440 describes a process for producing a film coated dosage form. A continuous groove is inscribed in a dosage form core. A latex film is coated onto the core, the groove defining a fixed zone and a detachable zone for the film. The detachable portion of the latex film detaches when it is exposed to the environment of use, thereby exposing a discrete portion of the dosage form core surface. The remainder of the film remains attached to the dosage form core. The exposed portion of the dosage form surface erodes and releases active agent to the environment of use.
Coated tablets for constant and prolonged active agent release are described by Conte et al in J. Controlled Release, Vol. 26, (1993) pages 39-47. These GEOMATRIX(trademark) Systems are swellable matrices that are coated or tableted with polymeric barrier layers. Release performances of the systems are modulated as a result of the reduction of the releasing surface exposed to the dissolution medium by the polymeric barrier layer coatings. As the extent of coating of the system""s surface is increased, the release kinetics of the system shift toward constant release. These systems are further described in U.S. Pat. No. 4,839,177 to Colombo et al.
U.S. Pat. No. 5,534,263, which is incorporated herein by reference, describes a dosage form useful for the prolonged delivery of an active agent formulation in the form of a matrix having two or more insoluble bands on the surface of the matrix. The exposed surfaces of the matrix erode in a manner that creates additional surface areas to provide for prolonged release of an active agent formulation with determined release profiles.
A layered tablet wherein at least one layer can swell by contact with biological fluids to prolong residence at the gastric level is described in U.S. Pat. No. 5,780,057.
Generally the foregoing systems have been directed to the delivery of active agents which are in the dosage forms initially in the dry state. Little effort appears to have been made to deliver liquid active agent formulations that would be retained in the stomach for a sustained period of time.
Administration of acyclovir by sipped solution over a four-hour period has been described in Br. J. clin. Pharmac., 21, 459-462 (1986) to achieve an increased contact time with the human stomach and the gastrointestinal tract. The total amount of acyclovir absorbed was increased over that observed with administration of acyclovir tablets. However, no attempt was made to maintain the acyclovir solution in the stomach for a sustained period except by continuous oral administration. Obviously, continuous oral administration is not a reasonable solution to the general problem of maintaining liquid active agent in the stomach for a sustained period of time.
Furthermore, when the active agent is insoluble or poorly soluble, prior art systems may not provide suitable delivery of active agent or concentration gradients at the site of absorption for that period of time that the active agent sees the absorption site. Various attempts have been made to address such problems, including the use of water-soluble salts, self-emulsifying compositions, polymorphic forms, powdered solutions, molecular complexes, micronization, eutectics, and solid solutions, in the context of immediate release delivery. An example of the use of a powdered solution is described by Sheth, et al., in xe2x80x9cUse of Powdered Solutions to Improve the Dissolution Rate of Polythiazide Tablets,xe2x80x9d Drug Development and Industrial Pharmacy, 16(5), 769-777 (1990). References to certain of the other approaches are cited therein. Additional examples of powdered solutions are described in U.S. Pat. No. 5,800,834. The patent describes methodology for calculating the amount of liquid that may be optimally sorbed into materials to prevent the drug solution from being exuded from the granular composition during compression.
U.S. Pat. No. 5,486,365, which is incorporated herein by reference, describes a spheronized material formed from a scale-like calcium hydrogen phosphate particulate material having a high specific surface area, good compressibility and low friability. That patent indicates that the material has the characteristic of high liquid absorption. However, the patent does not suggest that the material may be used as a carrier for delivery of a liquid medicament formulation to the environment of use. Instead, the patent describes the formation of a dried formulation, such as formed by spray drying. The patent describes the use of a suspension containing medicines and binders during the spray-drying granulation process to form a spherical particle containing the medicine. As an example, ascorbic acid in an amount equivalent to 10% of the scale-like calcium hydrogen phosphate was dissolved into a slurry of 20 weight percent of calcium hydrogen phosphate in water, and the resulting slurry was spray dried to form dried, spherical calcium hydrogen phosphate containing ascorbic acid. That material was then tableted under loads of 500-2000 kg/cm2.
As can be observed in the above-referenced patents and publications, devices have been described that provide for prolonged delivery of an active agent and retention in the gastric environment. However, there remains a continuing need for improved systems for delivering a liquid, active agent formulation to the gastric environment over a prolonged period of time and in a reliable, controllable and reproducible manner. In particular, there is a need for controlled release delivery devices that are to remain in the stomach, even during a fasting state in which IMMC is present, for a prolonged period, for example from about 3 hours to up to about 20-24 hours, and deliver a liquid, active agent formulation. Such devices should exhibit a combination of flexibility and rigidity so as not to be expelled from the stomach into the pyloric sphincter under fed or fasting conditions, and deliver active agent in a reproducible, controlled manner, over a prolonged period of time. One such device for delivering solid and liquid active agents has been described in our U.S. Pat. No. 6,120,803 pending U.S. application Ser. No. 09/131,923, filed Aug. 10, 1998, which is incorporated herein by reference.
Accordingly, the present invention is directed to a dosage form that will provide increased retention time of the device in the stomach over conventional dosage forms and release a liquid, active agent formulation in a reliably controllable manner, and further that is easy and inexpensive to manufacture.
In its broadest aspect, the invention comprises a dosage form having a liquid, active agent formulation absorbed in porous particles, the porous particles being dispersed in a bioerodible carrier adapted to be retained within the stomach of a subject for a prolonged period of time. Preferably, the porous particles exhibit low friability so as to resist compaction forces encountered during fabrication of the dosage form.
In another aspect, the invention comprises a dosage form having a liquid, active agent formulation absorbed in porous particles, the porous particles being dispersed in a bioerodible carrier that swells upon imbibing fluid from stomach so as to be retained within the stomach of a subject for a prolonged period of time.
In another aspect, the dosage form comprises a liquid, active agent formulation absorbed in porous particles, the porous particles being adapted to resist compaction forces sufficient to form a compacted layer without significant exudation of the liquid, active agent formulation admixed with a polymer matrix formed of a mixture of a swellable, water soluble polymer that expands when in contact with fluids in the gastric environment and a hydroattractant, preferably water insoluble. The matrix is formed with a rigid or semi-rigid segment in which swelling of the hydrogel is constrained to provide a rigid or semi-rigid section in the dosage form that facilitates the dosage form remaining in the stomach of a subject over a prolonged period of time. The liquid, active agent formulation is contained in porous particles having high porosity and superior resistance to compressive forces during fabrication of dosage form. In one embodiment, the rigid or semi-rigid section of the dosage form comprises one or more insoluble materials, typically exhibiting low water impermeability and formed as a band circumscribing a portion of the surface of the matrix, that along with the banded portion of the polymer matrix forms the rigid or semi-rigid segment of the dosage form.
The aforementioned insoluble material or band (or bands, if more than one band is utilized) prolongs the period of time in which the polymer matrix retains its integrity in an expanded state and increases the residence time of the dosage form in the stomach. As the dosage form erodes in the stomach or as active agent diffuses from the matrix, the porous particles containing the liquid, active agent formulation will be released over a prolonged period of time, and subsequently the active agent will be either absorbed by the stomach or passed from the stomach to the small intestine where it can be absorbed.
In still another aspect, the active agent dosage form comprises (a) a therapeutically-effective amount of a liquid, active agent formulation sorbed into a porous particle, (b) a polymer matrix in which the porous particle is dispersed, the polymer matrix including a high molecular weight, water-soluble polymer and a hydroattractant such as a water-insoluble polymer, and, optionally, non-polymeric water-soluble excipients and polymers of molecular weight of less than 10,000 grams per mole, the polymer matrix having an outer surface for exposure to the environment of use, and (c) at least one band of insoluble material circumscribing a portion of the outer surface of the polymer matrix.
In still another aspect, the invention comprises a dosage form adapted for gastric retention and delivery of a liquid, active agent formulation over a prolonged period comprising a polymer matrix formed of a water soluble, high molecular weight polymer and a hydroattractant in which the weight percent of the water soluble, high molecular weight polymer is about 10 to 50 weight percent and the weight percent of the hydroattractant is about 5 to 70 weight percent, and a plurality of porous particles containing the liquid, active agent formulation dispersed throughout the polymer matrix.
In a further aspect of the invention, the active agent dosage form comprises a unitary compressed dispersion of a liquid, active agent formulation in a plurality of porous particles in a gel-forming, erodible polymer matrix having a first portion that swells in the stomach while maintaining its physical integrity for a prolonged period of time and a second, non-erodible, non-gel-forming portion for promoting retention of the dosage form in the stomach over a prolonged period of time.
In yet another aspect, the invention comprises a dosage form having a liquid, active agent formulation absorbed in porous particles, the porous particles being dispersed in a bioerodible carrier adapted to be retained within the stomach of a subject for a prolonged period of time, the porous particles being selected from the group consisting of (i) particles, having a mean particle size of 50-150 microns, formed by spray drying a scale-like calcium hydrogen phosphate, having a specific surface area of 20 m2/g to 60 m2/g, an apparent specific volume of 1.5 ml/g or more, an oil absorption capacity of 0.7 ml/g or more, a primary particle size of 0.1xcexc to 5xcexc, and an average particle size of 2xcexc to 1xcexc among secondary particles that are aggregates of the primary particles, the scale-like calcium hydrogen phosphate being represented by the following general formula:
CaHPO4.mH2O 
wherein m satisfies the relationship 0xe2x89xa6mxe2x89xa62.0, and (ii) particles of magnesium aluminometasilicate represented by the general formula
Al2O3MgO.2SiO2.nH2O 
wherein n satisfies the relationship 0xe2x89xa6nxe2x89xa610 and having a specific surface area of about 100-300 m2/g, an oil absorption capacity of about 1.3-3.4 ml/g, a mean particle size of about 1-2 microns, an angle of repose about 25xc2x0-45xc2x0, a specific gravity of about 2 g/ml and a specific volume of about 2.1-12 ml/g.
In another aspect, the invention comprises a dosage form having a liquid, active agent formulation absorbed in porous particles, the porous particles being dispersed in a bioerodible carrier adapted to be retained within the stomach of a subject for a prolonged period of time, the porous particles being calcium hydrogen phosphate having a specific volume of at least 1.5 ml/g, a BET specific surface area of at least 20 m2/g, and a water absorption capacity of at least 0.7 ml/g. Preferably, the particles have a bulk density of 0.4-0.6 g/ml, a BET surface area of 30-50 m2/g, a specific volume of greater than 2 ml/g, and a mean pore size of at least 50 Angstroms.
In still another aspect, the invention comprises a dosage form having a liquid, active agent formulation absorbed in porous particles, the porous particles being dispersed in a bioerodible carrier adapted to be retained within the stomach of a subject for a prolonged period of time, the porous particles being calcium hydrogen phosphate having a specific volume of at least 1.5 ml/g, a BET specific area of at least 20 m2/g, and a water absorption capacity of at least 0.7 ml/g, the particles having a size distribution of 100% less than 40 mesh, 50%-100% less than 100 mesh and 10%-60% less than 200 mesh. Preferably, 100% is less than 40 mesh, 60%-90% is less than 100 mesh and 20%-60% is less than 200 mesh.
In another aspect, the invention comprises a dosage form having a liquid, active agent formulation absorbed in porous particles, the porous particles being dispersed in a bioerodible carrier adapted to be retained within the stomach of a subject for a prolonged period of time, the porous particles being calcium hydrogen phosphate having a bulk specific volume of 1.5 ml/g-5 ml/g, a BET specific area of 20 m2/g-60 m2/g, a water absorption capacity of at least 0.7 ml/g, and a mean particle size of at least 70 micrometers.
In another aspect, the dosage forms of the invention described above may comprise a gastric-emptying delaying agent, i.e., a substance that increases the retention time of the dosage form in the stomach. The gastric-emptying delaying agent may be combined with the composition containing the active agent for local delivery to the environment of use or it may be coated on the dosage form to provide the desired physiological response to delay onset of the IMMC and facilitate retention of the dosage form in the stomach.